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In patients with coronary artery disease (CAD) and diabetes mellitus, the treatment option is optimal medical therapy (OMT) either with or without revascularization. In 1996, a non–pre-specified subgroup analysis of 353 patients with diabetes mellitus from the BARI (Bypass Angioplasty Revascularization Investigation) trial showed a survival benefit of coronary artery bypass grafting (CABG) compared with percutaneous coronary intervention (PCI) (1), setting off a debate about PCI and CABG that has lingered on for decades. More recently, the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial showed a similar benefit of CABG over PCI, including reductions in myocardial infarction (MI) (p < 0.0001) and all-cause mortality (p = 0.049) (2). Consequently, the 2014 American College of Cardiology/American Heart Association guidelines (3) and the 2014 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines recommend CABG over PCI in patients with diabetes and multivessel disease (Class I) (4). Although this debate over the mode of revascularization has lingered on, the value of revascularization over OMT in patients with stable CAD has itself been questioned. In the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) study, a strategy of revascularization (CABG or PCI) + OMT was no better than OMT to reduce the risk of death or major cardiovascular events (MACE) (death, MI, or stroke) (5). Similarly, in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, PCI did not reduce the risk of death or MI, even in those with diabetes (6). However, in the BARI 2D trial, CABG reduced MACE over OMT, mainly driven by a significant reduction in MI (7.4% vs. 14.6%), but not mortality (14.0% vs. 16.9%) (5). Despite this, the 2014 American College of Cardiology/American Heart Association stable ischemic heart disease guidelines recommend OMT, even in patients with diabetes, and revascularization is recommended only in patients whose symptoms compromise quality of life, despite OMT (3).

So, how best to choose treatment options in patients with diabetes mellitus? Does a patient’s anatomy (number of diseased vessels, involvement of the proximal left anterior descending artery) or left ventricular ejection fraction (EF) guide the choice of therapy? Mancini et al. (7) in this issue of the Journal, present a few insights from a patient-level pooled analysis of the COURAGE (diabetes subgroup), BARI-2D, and FREEDOM trials (7). The strength of the analysis is the pooling of 3 well-conducted trials with potential for greater power for subgroup analysis. However, the numbers of patients in the subgroups were small (15% with EF <50% [largely between 35% and 50%], 28% with the proximal left anterior descending artery, and 48% with 3-vessel disease), and the test for treatment interaction by subgroup was not significant for all subgroups tested (pinteraction > 0.05). The overall conclusions of this pooling project are that CABG + OMT is the preferred choice over PCI + OMT or even OMT alone due to the reduction in MACE and the individual components of death (vs. PCI) and MI (vs. PCI or OMT), irrespective of EF and angiographic CAD burden. Could we have come to the same conclusion from the published main results of each of the 3 trials? Perhaps yes. The reduction in endpoints such as death or MI should be a compelling reason to choose 1 therapy over the other; that is, CABG + OMT should be preferred over OMT or PCI + OMT in all patients with diabetes. However, before we jump to this conclusion, how relevant are these trials done in the last decade to modern-day clinical practice? Critics would argue that the practice of PCI and CABG has advanced considerably, and so has the choice of OMT. Moreover, the considerable proportion of patients who crossed over from OMT alone to revascularization in the COURAGE (33%) and BARI 2D (42%) trials makes it harder to consider OMT alone as a treatment option, but more appropriately as an initial strategy, with revascularization needed in 1 out of every 2 or 3 patients.

The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study indicates that the risk of future cardiovascular events is equally attributable to recurrence at the site of the culprit lesion (12.9%) and to nonculprit lesions (11.6%), most of which were angiographically mild, emphasizing the need to aggressively treat both lesion subtypes (8). Of the 3 treatment strategies available, only OMT targets both angiographically significant and less significant lesions. However, there is no clear consensus as to what constitutes OMT, and there is controversy over whether all components of OMT (especially beta-blockers) reduce death or MI in patients with stable CAD without prior MI (9). Moreover, medication therapy is associated with adverse side effects, the individual response to therapy is variable, and the compliance rates are low. Thus, even in randomized trials, the achievement of OMT has been poor. In patients with diabetes, newer therapies (not used in the trials mentioned earlier), such as sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to reduce the risk of cardiovascular outcomes. Moreover, emerging data on proprotein convertase subtilisin/kexin type 9 inhibitors are encouraging, although results from the outcomes trials are eagerly awaited.

CABG targets angiographically significant lesions, but provides protection from less significant lesions as well (in the bypassed segment), whereas PCI targets angiographically significant lesions alone, which may explain some of the superior cardioprotection (for the outcome of MI) offered by CABG over PCI. In the current analysis, although 94% of patients who underwent CABG received an internal mammary graft, only 58% of those who underwent PCI received a drug-eluting stent (DES), all of which were first-generation DES. Newer-generation DES have thinner struts and thinner, more biocompatible polymers, which reduces inflammation and thrombogenicity, and promotes rapid endothelialization compared with first-generation DES (10).

Can the newer-generation DES bridge the mortality gap between PCI and CABG? The increased risk of events with PCI are due to “stent-related” events (restenosis, stent thrombosis, and neoatherosclerosis) as well as “non–stent-related” events (in segments not treated with a stent). Data from randomized trials (11), observational registries (12), and meta-analyses (11,13) indicate reduction in death, MI, and stent thrombosis with newer-generation stents compared with older-generation stents. Moreover, in the TUXEDO (Taxus Element versus Xience Prime in a Diabetic Population) trial of patients with diabetes mellitus randomized to PCI using paclitaxel-eluting stents (used in the FREEDOM trial) or an everolimus-eluting stent (EES) (second-generation DES), the EES was associated with significant reductions not only in target vessel failure (p = 0.005), but also in MI (p = 0.004), death or MI (p = 0.06), cardiac death or target vessel MI (p = 0.03), and stent thrombosis (p = 0.002) (14). It is therefore not surprising that in an indirect comparison analysis of 68 randomized trials, which enrolled 24,015 patients with diabetes with a total of 71,595 patient-years of follow-up, we showed that the mortality gap between PCI and CABG was reduced to nonsignificance when CABG was compared with PCI using newer–generation DES (15). Moreover, in a propensity score-matched analysis of patients who underwent CABG versus PCI using newer-generation DES (EES), we showed no significant mortality difference between CABG and PCI (16), even in the subset with diabetes (17). Although analysis from a registry cannot account for unmeasured confounders, data from over 3 decades of studies from the New York State registries show a remarkable reduction in the mortality gap between PCI and CABG with improvements in PCI technology (Figure 1). CABG will be hard to beat because of the superior protection against future events in the bypassed segment; however, the mortality gap between PCI and CABG can be lowered by using newer-generation DES to reduce “stent-related” events and aggressive OMT to reduce “non–stent-related” events.

Diminishing Mortality Gap Between PCI and CABG for Multivessel Disease From the New York State Registries

Outcomes with percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) for multivessel disease from the New York State registries published in the last 2 decades indicated a diminishing mortality gap between PCI and CABG. There was 40% to 50% lower mortality with CABG compared with plain old balloon angioplasty (POBA), which has progressively diminished to statistically nonsignificant when CABG is compared with PCI using newer-generation drug-eluting stents (DES). BMS = bare-metal stent; Gen = generation; JACC = Journal of the American College of Cardiology; NEJM = New England Journal of Medicine; NS = not significant.

Should the guidelines be changed to favor CABG + OMT in patients with diabetes given the reduction in MACE and MI in this analysis over OMT alone? Perhaps not. The superiority of CABG + OMT over OMT alone for the endpoints is driven by the BARI 2D CABG stratum, which included only 763 patients. The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial (NCT01471522) will compare an invasive strategy with cardiac catheterization and optimal revascularization plus OMT versus a conservative strategy with OMT alone; will have a large proportion of patients with diabetes mellitus; and has been designed to overcome prior strategy trial limitations, including enrollment of patients with higher ischemic burden and use of contemporary revascularization and medical therapy. The ISCHEMIA-CKD (ISCHEMIA-Chronic Kidney Disease) trial (NCT01985360), a parallel trial designed to test the same 2 treatment strategies in patients with chronic kidney disease (estimated glomerular filtration rate <30 ml/min/1.73 m2 or receiving dialysis) and ischemia, a large proportion of whom will have diabetes, will also provide important insights about treatment options in this important patient population. Until the results of these clinical trials are available, the choice between the 3 therapies should be on the basis of the pros and cons of each approach, ability to achieve complete revascularization with PCI, and patient preference.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

This paper refers to work supported by National Heart, Lung, and Blood Institute grants U01HL105907 and U01HL117905, in-kind donations from Abbott Vascular, Medtronic, Inc., St. Jude Medical, Volcano Corporation, Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, Merck Sharp & Dohme, and Omron Healthcare; and by financial donations from Arbor Pharmaceuticals and AstraZeneca Pharmaceuticals. Dr. Bangalore has reported grant support from the National Institutes of Health for the ISCHEMIA and the ISCHEMIA-CKD trials. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

(2014) 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol64:1929–1949.

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